1. Field of the Disclosure
The disclosure relates to novel spiro aminic compounds with Orexin 1 antagonist activity.
The disclosure also concerns a process for the preparation of those compounds, pharmaceutical compositions containing one or more compounds of Formula (VI) and their use as antagonists of the orexin 1 receptor.
2. Discussion of the Background Art
The orexins are neuropeptides discovered in 1998 from two research groups. Orexin A is a 33 aminic acid peptide while orexin B is a 28 aminic acid peptide. The orexins are secreted from a discrete group of neurons in the lateral hypothalamus and they bind to G-coupled receptors, namely OX1 and OX2. The orexin 1 receptor (OX1) binds selectively the orexin A, while the orexin 2 receptor (OX2) binds both orexin A and orexin B.
Orexins are known to stimulate food consumption in rats, thus suggesting their role as modulators in food intake mechanisms.
Moreover it has been shown that orexins regulate the sleep architecture, thus making them a novel therapeutic approach to narcolepsy, as a treatment for insomnia and other sleep disorders. It has been recently shown that orexins are involved in addiction mechanisms, thus their modulations will make possible the treatment of compulsive disorders and drug addictions. Orexin receptors are located in mammals brain and they are involved in several pathologies.
In the international patent application WO2009/016560 trans-3-aza-bicyclo[3.1.0]exane derivatives have been disclosed as a series of orexin antagonists.
Novel pyrrolidine and piperidine derivatives have been disclosed in WO2009/040730, N-aroil cyclic amine derivatives were disclosed in the international patent application WO02/090355 and piperazine compounds in WO03/051873, being all those novel structures proposed as antagonists of the orexin receptors.
A series of cyclic N-aroylamine derivatives has been disclosed in the international patent application WO2004/026866 as non-peptidic antagonists of the human orexin receptors. In particular 43 piperidine compounds, where the position beta to the nitrogen was substituted with hydrogen or methyl groups, have been tested for their activities against OX1 and OX2 receptors.
Those documents describe compounds with activity at both receptors.
The object of the present disclosure is to provide compounds with selective antagonist activity at the orexin 1 receptor.